Optically pure dihydropyrimidine compounds and their uses for the preparation of a medicament for treatment and prevention of viral diseases

Abstract

The present invention relates to an optically pure compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof, a process for preparing the optically pure compound of formula (I), and use of the optically pure compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof as a medicament, in particular as a medicament for the treatment and prevention of type B hepatitis.

1. A process for preparing an optically pure compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents hydrogen, 
         R 2  represents phenyl optionally substituted up to 5 times by fluoro, or thiazolyl optionally substituted by one or more substituents which are the same or different, and selected from: fluoro, chloro, bromo, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy, amino, and (C 1 -C 3 ) -acylamino, 
         R 3  represents phenyl, optionally substituted by one or more substituents which are the same or different, and selected from: fluoro, chloro, bromo, iodo, hydroxyl, trifluoromethyl, trifluoromethoxy, trifluoromethylsulfonyl, nitro, cyano, carboxy, and methoxycarbonyl, and 
         R 4  represents a group represented by formula —OR 11 , wherein R 11  represents hydrogen, (C 1 -C 3 )-alkenyl or (C 1 -C 4 )-alkyl, wherein the (C 1 -C 3 )-alkenyl and (C 1 -C 4 )-alkyl independently are optionally substituted by halogen, pyridyl, cyano, phenoxy, alkoxy, trifluoroethyl, benzyl or a group represented by formula —NR 15 R 16 , wherein R 15  and R 16 , the same or different, respectively represent hydrogen, benzyl or methyl, or a pharmaceutically acceptable salt thereof, comprising the steps of:
 1) reacting an amidine of formula (II) or a salt thereof 
 
       
       
         
           
           
               
               
           
         
         wherein R 2  is defined as above, with an aldehyde of formula (III) 
       
       
         
           
           
               
               
           
         
         wherein R 3  is defined as above, and a compound of formula (IV)
   CH 3 COCH 2 CONHCR 12 R 13 R 14  (IV) 
 
         wherein R 12 , R 13 , R 14  are different and respectively represent a substituent selected from hydrogen, substituted or unsubstituted phenyl, benzyl, or a straight or branched (C 1 -C 3 ) -hydrocarbyl, in the presence or absence of a base or acid, and in a suitable inert solvent, to obtain a compound of formula (V) 
       
       
         
           
           
               
               
           
         
         or 
         reacting a compound of formula (VI) or (VII) 
       
       
         
           
           
               
               
           
         
         wherein R 3 , R 12 , R 13 ,and R 14 are defined as above, with a compound of formula (II), in the presence or absence of a base or acid, at a temperature of 20-150° C., and in a suitable inert solvent, to obtain a compound of formula (V), 
         or
 reacting a aldehyde of formula (III) with a compound of formula (IV) and an iminoether of formula (VIII) 
 
       
       
         
           
           
               
               
           
         
         wherein R 2  is defined as above, and R′ is C 1 -C 4  alkyl, in the presence of an ammonium salt, to obtain a compound of formula (V), 
         2) acylating the compound of formula (V) in a suitable solvent, to obtain a compound of formula (IX) 
       
       
         
           
           
               
               
           
         
         wherein R 1  is (C 1 -C 6 )-acyl, arylacyl or arylsulfonyl, and R 2 , R 3 , R 12 , R 13  and R 14  are defined as above, and 
         3) the compound of formula (IX) is nitrosylated under an acidic or basic condition in a suitable solvent, and then reacted with sodium alkoxide R 11 ONa to obtain a optically pure compound of formula (I) 
       
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , and R 4  are defined as above. 
       
     
     
       2. The process of  claim 1  wherein the compound of formula (IV) CH 3 COCH 2 CONHCR 12 R 13 R 14 is prepared by a process comprising reacting a chiral primary amine R 12 R 13 R 14 CNH 2 with a diketene or diketene acetone adduct in the presence or absence of a base, and in an inert solvent, wherein R 12 , R 13 , and R 14  are as defined in  claim 1 . 
     
     
       3. The process of  claim 1  further comprising transferring the compound of formula (I) into a pharmaceutically acceptable salt thereof.